This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Editorial

Cell factories have been largely exploited for the controlled production of substances
of interest for food, pharma and biotech industries. Although human-controlled microbial
production and transformation are much older, the cell factory concept was fully established
in the 80’s through the intensive public and private investment. Strongly empowered
by the then nascent recombinant DNA technologies and supported by the approval of
recombinant insulin [1,2], the principle of controlled biological production as a convenient source of difficult-to-obtain
molecules (especially those of high added value) deeply penetrated the industrial
tissue, soon becoming a widespread platform aiming at cost-effective large-scale production
[3]. The first generation cell factories (mainly composed by plain strains of the bacterium
Escherichia coli and the yeast Saccharomyces cerevisae) were soon replaced by engineered variants. Resulting from the application of untargeted
mutagenesis and phenotypic selection, conventional genetic modification, metabolic
engineering, and more recently by systems metabolic engineering that integrates metabolic
engineering with systems biology and synthetic biology, new strains having much enhanced
performance have been progressively developed [4-19]. In parallel, mammalian and insect cells for the production of high quality proteins,
and other microbial species appealing from an industrial point of view due to their
unusual physiological traits, have been incorporated to the cell factory family [20,21]. This comprises algae, fungi, psychrophilic bacteria and moss, among others [22-26]. On the other hand, a set of food-grade lactic acid bacteria are under development
as emerging platforms in food microbiology but also as a novel source of metabolites
and proteins [27-34]. The physiological diversity of the microbial world offers an intricacy of biosynthetic
pathways from which novel bio-products, including nano- or micro-structured materials
[35-37], offer promises in even more diverse applications.

Still, many substances and materials of industrial interest are nowadays produced
by chemical synthesis, and the number of (recombinant) proteins approved for therapeutic
use hardly reaches 200, a figure much lower than that initially presumed. However,
both environmental concerns and medical and industrial needs strongly push towards
a fully sustainable bio-production of a larger spectrum of substances. Then, how much
limited is the economic feasibility of microbial production? Have the cell factories
reached a plateau in their development? Is there more room for further exploitation
of the microbial production?

Systems metabolic engineering [38,39] offers a set of methodological and strategic tools for the design and optimization
of metabolic and gene regulatory networks for the efficient production of chemicals
(from pharmaceuticals to bulk chemicals and fuels) and materials (from plastics to
high value materials) [5-7,40]. Furthermore, creation of new metabolic pathways and fine tuning of the existing
ones have become possible [8,15]. This is already allowing the production of substances so far reluctant to microbial
production under industrial requirements and under cost-effective processes, allowing
us to overcome limitations of microbial cell factories. In silico genome-scale metabolic modeling and simulation are playing increasingly important
roles in system-wide identification of target genes and pathways to be manipulated
to enhance production of desired products. Profiling of transcriptome, proteome, metabolome,
and/or fluxome is also becoming a routine practice in metabolic engineering for the
better understanding of cellular characteristics under given genetic and/or environmental
perturbations. Through the system-wide optimized design and development of microbial
cell factories, many industrially important chemicals and materials could be efficiently
produced. Some example products include, but not limited to, alcohols other than ethanol
including propanol, butanol and isobutanol, dicarboxylic acids such as succinic acid,
fumaric acid, malic acid and adipic acid, diols such as 1,3-propanediol, 1,2-propanediol,
1,4-butanediol and 2,3-butanediol, diamines such as putrescine and cadaverine, and
even polymers including polyhydroxyalkanoates, polylactic acid, spider silk protein,
poly-gamma-glutamic acid, and many others [40]. It is expected that increasingly diverse chemicals and materials that are currently
produced by petrochemical industry will be produced by employing microbial cell factories.

Improving cell factories by systems biotechnology to an industrially relevant level
cannot be successfully reached by individual teams alone. A wide range of expertise
is needed for the full development of a novel biotechnological process, including
microbiology, chemistry, bioinformatics, biochemical engineering, but also agricultural
and plant sciences and economics. After a proof of concept has shown the feasibility
of a novel approach for cell factory engineering, large consortia or networks of fully
skilled teams should take over in collaboration with Biotech companies to accomplish
an economically feasible bioprocess. As an early example, the development of bacteria
producing 1,3-propanediol from glucose has been well documented, and required the
engineering of more than 70 genes, before process development and scale up were reasonably
made [41]. Replacing materials which are produced from mineral oil by biobased products requires
not only efficient technology but also the assessment of economical and ecological
feasibility, as intensely studied for polylactic acid [42].

As the progress of industrial biotechnology did not accomplish the desired speed of
development [43] academic researchers have teamed up with industry in publicly funded research centers
worldwide. To name a few, the Joint BioEnergy Institute (JBEI) in the San Francisco
Bay Area, the Novo Nordisk Foundation Center for Biosustainability (CFB) at the Technical
University of Denmark, the Metabolic and Biomolecular Engineering Laboratory (MBEL)
of the Korea Advanced Institute of Science and Technology (KAIST), the Dutch Klyuver
Centre for Genomics of Industrial Fermentation, or the Austrian Centre of Industrial
Biotechnology (ACIB) share the mission to speed up development of industrial bioprocesses
by joining forces of different academic disciplines with industrial collaborators.